The formation of arteriosclerotic lesions in arterial blood vessels is the underlying disease for a large range of clinical symptoms which extend from angina pectoris via intermittent claudication to myocardial infarction and ischemic stroke; all based on atheroma formation and/or stenotic lesions. The term stenotic lesions refers to the local reduction of the vascular lumen to less than 60-70% of its normal diameter, which in turn leads to a marked reduction in the supply of oxygen and nutrients to the particular tissue. Although pharmacotherapy (statins, ACE inhibitors, gpIIa/IIIb blockers and plasminogen activators) have shown good therapeutic results especially in the area of cardiovascular diseases in recent decades, surgical interventions (bypass operations, etc.) are still necessary for many patients who have developed a complete ischemic state. These operations are moreover relatively complicated and costly and involve the risk of serious complications.
Minimally invasive surgical methods have been developed in order to prevent the development of ischemic heart diseases. The invention of percutaneous transluminal coronary angioplasty (PCTA) in the late 1970s was a great breakthrough in cardiology. PTCA involves the use of inflatable balloons which are advanced as far as the stenotic lesion in the coronary arteries. These balloons are then inflated at the particular target positions and achieve dilatation of the stenotic region. A similar procedure can also be used for dilation of carotid or peripheral arteries.
Despite this, it was found relatively soon that a recurrent stenosis developed in a relatively large proportion of PTCA patients at the sites which had been dilated with the balloon catheter. It was discovered in this connection that this so-called restenosis arises through reorganization of the vascular architecture of the tissue layers. The introduction of tubular vascular metal implants, so-called stents, in the transluminal treatment of stenosis improved the situation. It has been demonstrated in clinical studies (Serruys et al., N. Engl. J. Med. 331 (1994) 489-495) that the use of stents at the balloon-dilated sites was able to reduce the occurrence of restenosis from about 45% to about 30%. Although this is to be regarded as a significant improvement in the prevention of residual restenosis, there is still a distinct stimulus for therapeutic improvements.
It was discovered in detailed studies of the pathophysiology of restenosis in the stent that this differs from PTCA-induced restenosis. Inflammatory reactions, hyperproliferation and in-migration of smooth muscle cells (SMCs) are important factors in neointima formation which lead to restenosis in the stent. It has been found in the animal model of restenosis and even in human tissue that the hyperproliferation of the SMCs is associated with infiltration of macrophages and T cells into the tissue around the reinforcements of the stent (Grewe et al., J. Am. Coll. Cardiol. 35 (2000) 157-63).
In analogy to other clinical indications where inflammatory reactions and hyperproliferation of cells are involved and which can be controlled by medical treatment, attempts have also been made to treat restenosis by pharmacotherapy. Selected active agents have been given either orally or intravenously or brought to the site of action through perforated catheters. Unfortunately, to date none of these active agents have been able to reduce restenosis significantly (Gruberg et al., Exp. Opin. Invest. Active agents 9 (2000) 2555-2578).
Direct delivery of pharmacologically active agents from active agent-coated stents is one active area of investigation. Animal experiments and initial results of clinical trials with active agent-coated stents give the impression that delayed release of immunosuppressive and/or antiproliferative active agents can reduce the risk of restenosis. Paclitaxel, a cytotoxic active agent, and rapamycin, an immunosuppressive and cytostatic active agent, have been tested in animal experiments. Both compounds are reported to inhibit neointima formation (Herdeg et al., Semin Intervent Cardiol 3 (1998) 197-199; Hunter et al., Adv. Active agent. Delivery Rev. 26 (1997) 199-207; Burke et al., J. Cardiovasc Pharmacol., 33 (1999) 829-835; Gallo et al., Circulation 99 (1999) 2164-2170). Nevertheless, the beneficial effect has been observed to cease after 6 months of implantation of coated stents in pigs with paclitaxel (Heldman, International Local Active agent Delivery Meeting and Cardiovascular Course on Radiation, Geneva, Jan. 25-27, 2001).
Rapamycin showed good efficacy with complete abolition of restenosis in initial clinical applications (Sousa et al., Circulation 103 (2001) 192-195). On the other hand, this agent delays healing of vessel wall injury caused by balloon angioplasty and stent implantation.
In view of the foregoing, it would be desirable to provide medical implants that balance the effects of healing of the arterial vessel wall after angioplasty and stent placement with controlling neointima formation.
It further would be desirable to provide active agents that achieve this balance by selectively interfering with specific mechanisms leading to neointima formation.
It would also further be desirable to provide implants with favorable properties for the treatment and prophylaxis of restenosis.